Transcriptomics-Based Exploration on the Protective Mechanism of GLP-1 Receptor Agonist on Glomerular Mesangial Cells
Objective To explore the protective mechanism of glucagon-like peptide-1 receptor agonist(GLP-1RA)against diabetic kidney injury.Methods In this study,mouse glomerular mesangial cells(MCs)were selected for in vitro study,and the glomerular MCs were divided into the control group(Group C),the high-glucose and high-fat treatment group(Group GP)and the GLP-1RA exendin-4 treat-ment group(Group EX-GP).The cell viability was measured by CCK-8;the transcriptome of the cells was sequenced by RNA-seq;the gene expression of phosphofructokinase(Pfk),citrate synthase(Cs),α-ketoglutarate dehydrogenase(Ogdh),microtubule-associated protein light chain 3(LC3),recombinant gene expression of human autophagy effector protein(Beclin-1),mitochondrial DNA(mtDNA),silencing information regulator 1(Sirt-1)and peroxisome proliferator-activated receptor-assisted activator 1α(Pgc-1α)were determined by qRT-PCR.Results In the high glucose and high fat-induced glomerular MCs injury model,the survival rate of MCs was reduced in the GP group and restored in the EX-GP group.By using RNA-seq,there were significant gene expression differences among Group C,GP and EX-GP.By KEGG enrichment analysis,the gene differential expression pathways involved cellular fatty acid metabolism,mTOR signaling pathway,autophagy and so on.The expression of Pfk gene was inhibited in GP group,but its expression could partially restore in the EX-GP group(P＜0.05).After exendin-4 treatment,mtDNA gene expression was increased(P＜0.05),and the expressions of autophagy related genes LC3 and Beclin-1 were significantly increased(P＜0.05).The expression of Sirt-1 and Pgc-1α genes in EX-GP group was increased compared with GP group(P＜0.05).Conclusion RNA-seq and energy metabolism-related gene studies suggested that the mechanism of GLP-1RA exendin-4 amelio-ration of high-glucose and high-fat-induced injury in MCs may involve the energy metabolism-related signaling pathway and the expression of Sirt-1,Pgc-1α,autophagy and glycolysis genes.
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